Postoperative Outcomes After Gastrointestinal Surgery in Patients Receiving Chronic Kidney Replacement Therapy: A Population-based Cohort Study.

OBJECTIVE: This study evaluated the postoperative mortality and morbidity outcomes following the different subtypes of gastrointestinal (GI) surgery over a 15-year period. BACKGROUND: Patients receiving chronic kidney replacement therapy (KRT) experience higher rates of general surgery compared with other surgery types. Contemporary data on the types of surgeries and their outcomes are lacking. KRT was defined as patients requiring chronic dialysis (hemodialysis or peritoneal dilaysis) or having a functioning kidney transplant long-term. METHODS: All incident and prevalent patients aged greater than 18 years identified in the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry as receiving chronic KRT were linked with jurisdictional hospital admission datasets between January 1, 2000 until December 31, 2015. Patients were categorized by their KRT modality [hemodialysis (HD), peritoneal dialysis (PD), home hemodialysis (HHD), and kidney transplant (KT)]. GI surgeries were categorized as upper gastrointestinal (UGI), bowel (small and large bowel), anorectal, hernia surgery, cholecystectomy, and appendicectomy. The primary outcome was the rates of the different surgeries, estimated using Poisson models. Secondary outcomes were risks of 30-day/in-hospital postoperative mortality risk and nonfatal outcomes and were estimated using logistic regression. Independent predictors of 30-day mortality were examined using comorbidity-adjusted Cox models. RESULTS: Overall, 46,779 patients on chronic KRT were linked to jurisdictional hospital datasets, and 9,116 patients were identified as having undergone 14,540 GI surgeries with a combined follow-up of 76,593 years. Patients on PD had the highest rates of GI surgery (8 per 100 patient years), with hernia surgery being the most frequent. Patients on PD also had the highest risk of 30-day postoperative mortality following the different types of GI surgery, with the risk being more than 2-fold higher after emergency surgery compared with elective procedures. Infective postoperative complications were more common than cardiac complications. This study also observed a U-shaped association between body mass index (BMI) and mortality, with a nadir in the 30 to 35 kg/m 2 group. CONCLUSIONS: Patients on chronic KRT have high rates of GI surgery and morbidity, particularly in those who receive PD, are older, or are either underweight or moderately obese.

AcceSS and Equity in Transplantation (ASSET) New Zealand: Protocol for population-wide data linkage platform to investigate equity in access to kidney failure health services in New Zealand.

BACKGROUND: Kidney transplantation is considered the ideal treatment for most people with kidney failure, conferring both survival and quality of life advantages, and is more cost effective than dialysis. Yet, current health systems may serve some people better than others, creating inequities in access to kidney failure treatments and health outcomes. AcceSS and Equity in Transplantation (ASSET) investigators aim to create a linked data platform to facilitate research enquiry into equity of health service delivery for people with kidney failure in New Zealand. METHODS: The New Zealand Ministry of Health will use patients' National Health Index (NHI) numbers to deterministically link individual records held in existing registry and administrative health databases in New Zealand to create the data platform. The initial data linkage will include a study population of incident patients captured in the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), New Zealand Blood Service Database and the Australia and New Zealand Living Kidney Donor Registry (ANZLKD) from 2006 to 2019 and their linked health data. Health data sources will include National Non-Admitted Patient Collection Data, National Minimum Dataset, Cancer Registry, Programme for the Integration of Mental Health Data (PRIMHD), Pharmaceutical Claims Database and Mortality Collection Database. Initial exemplar studies include 1) kidney waitlist dynamics and pathway to transplantation; 2) impact of mental illness on accessing kidney waitlist and transplantation; 3) health service use of living donors following donation. CONCLUSION: The AcceSS and Equity in Transplantation (ASSET) linked data platform will provide opportunity for population-based health services research to examine equity in health care delivery and health outcomes in New Zealand. It also offers potential to inform future service planning by identifying where improvements can be made in the current health system to promote equity in access to health services for those in New Zealand.

One-Time Fecal Immunochemical Screening for Advanced Colorectal Neoplasia in Patients with CKD (DETECT Study).

BACKGROUND: In patients with CKD, the risk of developing colorectal cancer is high and outcomes are poor. Screening using fecal immunochemical testing (FIT) is effective in reducing mortality from colorectal cancer, but performance characteristics of FIT in CKD are unknown. METHODS: To determine the detection rates and performance characteristics of FIT for advanced colorectal neoplasia (ACN) in patients with CKD, we used FIT to prospectively screen patients aged 35-74 years with CKD (stages 3-5 CKD, dialysis, and renal transplant) from 11 sites in Australia, New Zealand, Canada, and Spain. All participants received clinical follow-up at 2 years. We used a two-step reference standard approach to estimate disease status. RESULTS: Overall, 369 out of 1706 patients who completed FIT (21.6%) tested positive; 323 (87.5%) underwent colonoscopies. A total of 1553 (91.0%) completed follow-up; 82 (4.8%) had died and 71 (4.2%) were lost. The detection rate of ACN using FIT was 6.0% (5.6%, 7.4%, and 5.6% for stages 3-5 CKD, dialysis, and transplant). Sensitivity, specificity, and positive and negative predictive values of FIT for ACN were 0.90, 0.83, 0.30, and 0.99, respectively. Of participants who underwent colonoscopy, five (1.5%) experienced major colonoscopy-related complications, including bowel perforation and major bleeding. CONCLUSIONS: FIT appears to be an accurate screening test for patients with CKD, such that a negative test may rule out the diagnosis of colorectal cancer within 2 years. However, the risk of major complications from work-up colonoscopy are at least ten-fold higher than in the general population.

Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients.

BACKGROUND: Prolonging kidney transplant survival is an important clinical priority. Induction immunosuppression with antibody therapy is recommended at transplantation and non-depleting interleukin-2 receptor monoclonal antibodies (IL2Ra) are considered first line. It is suggested that recipients at high risk of rejection should receive lymphocyte-depleting antibodies but the relative benefits and harms of the available agents are uncertain. OBJECTIVES: We aimed to: evaluate the relative and absolute effects of different antibody preparations (except IL2Ra) when used as induction therapy in kidney transplant recipients; determine how the benefits and adverse events vary for each antibody preparation; determine how the benefits and harms vary for different formulations of antibody preparation; and determine whether the benefits and harms vary in specific subgroups of recipients (e.g. children and sensitised recipients). SEARCH METHODS: Randomised controlled trials (RCTs) comparing monoclonal or polyclonal antibodies with placebo, no treatment, or other antibody therapy in adults and children who had received a kidney transplant. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing monoclonal or polyclonal antibodies with placebo, no treatment, or other antibody therapy in adults and children who had received a kidney transplant. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed risk of bias. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) together with their 95% confidence intervals (CI). MAIN RESULTS: We included 99 studies (269 records; 8956 participants; 33 with contemporary agents). Methodology was incompletely reported in most studies leading to lower confidence in the treatment estimates.Antithymocyte globulin (ATG) prevented acute graft rejection (17 studies: RR 0.63, 95% CI 0.51 to 0.78). The benefits of ATG on graft rejection were similar when used with (12 studies: RR 0.61, 0.49 to 0.76) or without (5 studies: RR 0.65, 0.43 to 0.98) calcineurin inhibitor (CNI) treatment. ATG (with CNI therapy) had uncertain effects on death (3 to 6 months, 3 studies: RR 0.41, 0.13 to 1.22; 1 to 2 years, 5 studies: RR 0.75, 0.27 to 2.06; 5 years, 2 studies: RR 0.94, 0.11 to 7.81) and graft loss (3 to 6 months, 4 studies: RR 0.60, 0.34 to 1.05; 1 to 2 years, 3 studies: RR 0.65, 0.36 to 1.19). The effect of ATG on death-censored graft loss was uncertain at 1 to 2 years and 5 years. In non-CNI studies, ATG had uncertain effects on death but reduced death-censored graft loss (6 studies: RR 0.55, 0.38 to 0.78). When CNI and older non-CNI studies were combined, a benefit was seen with ATG at 1 to 2 years for both all-cause graft loss (7 studies: RR 0.71, 0.53 to 0.95) and death-censored graft loss (8 studies: RR 0.55, 0.39 to 0.77) but not sustained longer term. ATG increased cytomegalovirus (CMV) infection (6 studies: RR 1.55, 1.24 to 1.95), leucopenia (4 studies: RR 3.86, 2.79 to 5.34) and thrombocytopenia (4 studies: RR 2.41, 1.61 to 3.61) but had uncertain effects on delayed graft function, malignancy, post-transplant lymphoproliferative disorder (PTLD), and new onset diabetes after transplantation (NODAT).Alemtuzumab was compared to ATG in six studies (446 patients) with early steroid withdrawal (ESW) or steroid minimisation. Alemtuzumab plus steroid minimisation reduced acute rejection compared to ATG at one year (4 studies: RR 0.57, 0.35 to 0.93). In the two studies with ESW only in the alemtuzumab arm, the effect of alemtuzumab on acute rejection at 1 year was uncertain compared to ATG (RR 1.27, 0.50 to 3.19). Alemtuzumab had uncertain effects on death (1 year, 2 studies: RR 0.39, 0.06 to 2.42; 2 to 3 years, 3 studies: RR 0.67, 95% CI 0.15 to 2.95), graft loss (1 year, 2 studies: RR 0.39, 0.13 to 1.30; 2 to 3 years, 3 studies: RR 0.98, 95% CI 0.47 to 2.06), and death-censored graft loss (1 year, 2 studies: RR 0.38, 0.08 to 1.81; 2 to 3 years, 3 studies: RR 2.45, 95% CI 0.67 to 8.97) compared to ATG. Creatinine clearance was lower with alemtuzumab plus ESW at 6 months (2 studies: MD -13.35 mL/min, -23.91 to -2.80) and 2 years (2 studies: MD -12.86 mL/min, -23.73 to -2.00) compared to ATG plus triple maintenance. Across all 6 studies, the effect of alemtuzumab versus ATG was uncertain on all-cause infection, CMV infection, BK virus infection, malignancy, and PTLD. The effect of alemtuzumab with steroid minimisation on NODAT was uncertain, compared to ATG with steroid maintenance.Alemtuzumab plus ESW compared with triple maintenance without induction therapy had uncertain effects on death and all-cause graft loss at 1 year, acute rejection at 6 months and 1 year. CMV infection was increased (2 studies: RR 2.28, 1.18 to 4.40). Treatment effects were uncertain for NODAT, thrombocytopenia, and malignancy or PTLD.Rituximab had uncertain effects on death, graft loss, acute rejection and all other adverse outcomes compared to placebo. AUTHORS' CONCLUSIONS: ATG reduces acute rejection but has uncertain effects on death, graft survival, malignancy and NODAT, and increases CMV infection, thrombocytopenia and leucopenia. Given a 45% acute rejection risk without ATG induction, seven patients would need treatment to prevent one having rejection, while incurring an additional patient experiencing CMV disease for every 12 treated. Excluding non-CNI studies, the risk of rejection was 37% without induction with six patients needing treatment to prevent one having rejection.In the context of steroid minimisation, alemtuzumab prevents acute rejection at 1 year compared to ATG. Eleven patients would require treatment with alemtuzumab to prevent 1 having rejection, assuming a 21% rejection risk with ATG.Triple maintenance without induction therapy compared to alemtuzumab combined with ESW had similar rates of acute rejection but adverse effects including NODAT were poorly documented. Alemtuzumab plus steroid withdrawal would cause one additional patient experiencing CMV disease for every six patients treated compared to no induction and triple maintenance, in the absence of any clinical benefit. Overall, ATG and alemtuzumab decrease acute rejection at a cost of increased CMV disease while patient-centred outcomes (reduced death or lower toxicity) do not appear to be improved.

A population pharmacokinetic model to predict oxypurinol exposure in patients on haemodialysis.

PURPOSE: The aims of this study were to characterise the population pharmacokinetics of oxypurinol in patients receiving haemodialysis and to compare oxypurinol exposure in dialysis and non-dialysis patients. METHODS: Oxypurinol plasma concentrations from 6 gout people receiving haemodialysis and 19 people with gout not receiving dialysis were used to develop a population pharmacokinetic model in NONMEM. Deterministic simulations were used to predict the steady-state area under the oxypurinol plasma concentration time curve over 1 week (AUC7days). RESULTS: The pharmacokinetics of oxypurinol were best described by a one-compartment model with a separate parameter for dialytic clearance. Allopurinol 100 mg daily produced an AUC7days of 279 µmol/L h in dialysis patients, a value 50-75 % lower than the AUC7days predicted for patients with normal renal function taking 200 to 400 mg daily (427-855 µmol/L h). Dosing pre-dialysis resulted in about a 25-35 % reduction in exposure compared to post-dialysis. CONCLUSIONS: Oxypurinol is efficiently removed by dialysis. The population dialytic and total (non-dialytic) clearance of oxypurinol were found to be 8.23 and 1.23 L/h, standardised to a fat-free mass of 70 kg and creatinine clearance of 6 L/h, respectively. Our results suggest that if the combination of low-dose allopurinol and haemodialysis does not result in sustained urate lowering below treatment targets (serum urate ≤0.36 mmol/L), then allopurinol doses may be increased to optimise oxypurinol exposure.

Dynamic changes in myeloid derived suppressor cell subsets following renal transplant: A prospective study.

BACKGROUND: Myeloid-derived suppressor cells (MDSC) are powerful suppressors of immune responses. MDSC numbers are increased in some renal transplant recipients (RTR) and there is increasing interest in their potential role in promoting both transplant tolerance and transplant associated malignancy. However the factors influencing MDSC mobilisation are unknown, and the relative temporal changes in the granulocytic (G-MDSC) and monocytic (Mo-MDSC) subsets of MDSC have not been defined. METHODS: The circulating frequencies of MDSC and dendritic cells (DC) were analysed by multicolour flow cytometry in RTR (n = 8) prior to transplant and at regular intervals out to 1 year post-transplant. RESULTS: In RTRs, numbers of both G-MDSC and Mo-MDSC increased rapidly following transplant and peaked within 8 days, whilst DC numbers decreased. A second peak in G-MDSC numbers was observed in 7/8 patients within 3 months and 2 patients had a further 3rd peak in G-MDSC numbers which, in one patient, corresponded to a rejection event. Mo-MDSC numbers underwent less fluctuation and a subsequent peak in numbers was observed in only 2/8 patients. Respective kidney donors (n = 5) underwent only small transient increases in MDSC following surgery. Overall, there was little correlation between increases in MDSC and the occurrence of detectable clinical events or treatment changes. CONCLUSIONS: In RTRs, MDSC numbers increase rapidly and peak following commencement of immunosuppression, but then fluctuate in response to as yet undefined stimuli. Further studies are required to identify the factors modulating MDSC mobilisation.

Renal replacement therapy associated with lithium nephrotoxicity in New Zealand.

AIM: To document the numbers and characteristics of New Zealand patients commencing renal replacement therapy because of end-stage kidney disease attributed to lithium treatment, and to calculate incidence rates. METHOD: Data on such patients were provided by the Australia and New Zealand Dialysis and Transplant Registry from the start of the Registry in 1977 until 2013. Numbers of patients prescribed lithium in the community were provided by the Ministry of Health for 2009-2013; earlier years had fewer than 96% of prescriptions for lithium linked to individuals by their unique National Health Index number. Time trends were analysed by linear, logistic and Poisson regression. Incidence rates were also calculated for five-year periods. RESULTS: Thirty-five new patients were located with 'lithium toxicity' as their primary renal disease, starting the year after 'lithium toxicity' was included in the standard list (1995). A broader search for lithium within 'other' causes and 'other' comorbidities did not yield further patients. The mean age at the start of renal replacement therapy was 61.1 years (SD 9.2). Twenty-five patients were female. For 1996 onwards, new patient numbers increased on average by 8% per year (95% CI 1 to 15%) and incidence rates increased by 7% per year (95% CI 0 to 14%), an approximate doubling per decade. Form 2007-2011, the average annual incidence per million population was 0.74 (95% CI 0.43 to 1.21) for New Zealand, similar to that reported elsewhere: 0.78 (95% CI 0.67 to 0.90) for Australia and 0.91 (95% CI 0.50 to 1.52) for southern Sweden. Prescription rates across the three countries were also similar. In New Zealand between 2009 and 2013, over 7,500 patients were prescribed lithium each year. CONCLUSION: Dosing and monitoring of patients prescribed lithium should follow guidelines, not only to avoid future psychiatric episodes and acute toxicity but also because such adherence may reduce uncommon but serious outcomes of long-term treatment such as end-stage kidney disease.

Treatment for peritoneal dialysis-associated peritonitis.

BACKGROUND: Peritonitis is a common complication of peritoneal dialysis (PD) that is associated with significant morbidity including death, hospitalisation, and need to change from PD to haemodialysis. Treatment is aimed to reduce morbidity and recurrence. This is an update of a review first published in 2008. OBJECTIVES: To evaluate the benefits and harms of treatments for PD-associated peritonitis. SEARCH METHODS: For this review update we searched the Cochrane Renal Group's Specialised Register to March 2014 through contact with the Trials Search Co-ordinator using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE and EMBASE, and handsearching conference proceedings. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs assessing the treatment of peritonitis in PD patients (adults and children). We included any study that evaluated: administration of an antibiotic by different routes (e.g. oral, intraperitoneal (IP), intravenous (IV)); dose of an antibiotic agent; different schedules of administration of antimicrobial agents; comparisons of different regimens of antimicrobial agents; any other intervention including fibrinolytic agents, peritoneal lavage and early catheter removal. DATA COLLECTION AND ANALYSIS: Multiple authors independently extracted data on study risk of bias and outcomes. Statistical analyses were performed using the random effects model. We expressed summarised treatment estimates as a risk ratio (RR) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous outcomes. MAIN RESULTS: We identified 42 eligible studies in 2433 participants: antimicrobial agents (36 studies); urokinase (4 studies), peritoneal lavage (1 study), and IP immunoglobulin (1 study). We did not identify any optimal antibiotic agent or combination of agents. IP glycopeptides (vancomycin or teicoplanin) had uncertain effects on primary treatment response, relapse rates, and need for catheter removal compared to first generation cephalosporins, although glycopeptide regimens were more likely to achieve a complete cure (3 studies, 370 episodes: RR 1.66, 95% CI 1.01 to 2.72). For relapsing or persistent peritonitis, simultaneous catheter removal and replacement was better than urokinase at reducing treatment failure rates (RR 2.35, 95% CI 1.13 to 4.91) although evidence was limited to a single small study. Continuous and intermittent IP antibiotic dosing schedules had similar treatment failure and relapse rates. IP antibiotics were superior to IV antibiotics in reducing treatment failure in one small study (RR 3.52, 95% CI 1.26 to 9.81). Longer duration treatment (21 days of IV vancomycin and IP gentamicin) had uncertain effects on risk of treatment relapse compared with 10 days treatment (1 study, 49 patients: RR 1.56, 95% CI 0.60 to 3.95) although may have increased ototoxicity.In general, review conclusions were based on a small number of studies with few events in which risk of bias was generally high; interventions were heterogeneous, and outcome definitions were often inconsistent. There were no RCTs evaluating optimal timing of catheter removal and data for automated PD were absent. AUTHORS' CONCLUSIONS: Many of the studies evaluating treatment of PD-related peritonitis are small, out-dated, of poor quality, and had inconsistent definitions and dosing regimens. IP administration of antibiotics was superior to IV administration for treating PD-associated peritonitis and glycopeptides appear optimal for complete cure of peritonitis, although evidence for this finding was assessed as low quality. PD catheter removal may be the best treatment for relapsing or persistent peritonitis.Evidence was insufficient to identify the optimal agent, route or duration of antibiotics to treat peritonitis. No specific antibiotic appears to have superior efficacy for preventing treatment failure or relapse of peritonitis, but evidence is limited to few trials. The role of routine peritoneal lavage or urokinase is uncertain.

Effect of activated human polymorphonuclear leucocytes on T lymphocyte proliferation and viability.

Human polymorphonuclear leucocytes (PMN) are thought to be immunosuppressive. The suppressive mechanism(s) used by PMN are, however, not well defined and in this study they were analysed using T-cell responses to CD3(+) CD28 monoclonal antibodies (mAb) as a readout. We demonstrate that in vitro activated PMN (PMN(act)) can, without any T-cell interaction, induce apparent T-cell suppression by inhibiting the stimulatory capacity of the CD3 mAb. However, a cell-directed suppression of T-cell proliferation was observed when PMN(act) were added to pre-activated T cells that are already committed to polyclonal proliferation. This suppression was partially reversed by catalase addition (P < 0·01) and largely reversed by addition of exogenous interleukin-2 (P < 0·001) but was not significantly reduced by nitric oxide synthase inhibition, myeloperoxidase inhibition or addition of excess arginine. Following removal of PMN(act) , suppressed T cells could respond normally to further stimulation. In addition to suppressing proliferation, co-culture with PMN(act) also induced a significant decrease in T-cell viability that was reversed by catalase addition (P < 0·05). The addition of the arginase inhibitor N-hydroxy-nor-l-arginine induced both a further significant, catalase-sensitive, loss in T-cell viability and increased nitrite release (P < 0·001). These data demonstrate that PMN, when activated, can both induce T-cell death and reversibly inhibit proliferation of activated T cells. The mechanisms underlying these distinct processes and the effects of arginase inhibitors on PMN induced cytotoxicity merit further investigation.

The experiences of commercial kidney donors: thematic synthesis of qualitative research.

Commercial transplantation has expanded because of the shortage of kidneys for transplantation. This study aims to synthesize qualitative studies on the experiences and perspectives of living commercial kidney donors. We conducted a comprehensive literature search in electronic databases to April 2011 and consulted experts to identify unpublished studies. Thematic synthesis was used to analyze the findings. Seven studies involving over 676 commercial kidney donors were included. Three major themes were identified: desperation (the participants' decision to sell their kidney was forced by poverty, debt, or to fulfill a family obligation); despair (destroyed body integrity, shame and secrecy, dehumanized and dispirited, loss of livelihood, heightened sense of vulnerability, disappointment, and regret); and debasement (deception by brokers and recipients, victimized by the hospital, stigmatized by community, and rejected by family). Commercial kidney transplantation is reported to result in ramifications for the donors' mental, physical, and social well-being. Not only do they remain in poverty, they lose dignity, sense of purpose, respect, relationships, and livelihood. Review of this published literature supports the need for effective implementation of the WHO guiding principles and legislated regulation to deter potential recipients and healthcare providers from pursuing commercial transplantation.

Renal transplant recipients have elevated frequencies of circulating myeloid-derived suppressor cells.

BACKGROUND: Cancer, particularly cutaneous squamous cell carcinoma (SCC), is a major cause of mortality in renal transplant recipients (RTRs). Myeloid-derived suppressor cells (MDSC) play a central role in suppressing cancer immunosurveillance but their potential mobilisation in RTRs and levels relative to those of other immunoregulatory dendritic cell (DC) populations have not been analysed. METHODS: The circulating frequencies of MDSC and DC were analysed by multicolour flow cytometry in immunocompetent patients without (n = 13) or with (ICI-SCC(Pos), n = 14) current SCC, normal donors (NDs, n = 34), chronic kidney disease patients (CKD patients, n = 22) and RTRs (n = 31). RESULTS: Compared to NDs, RTRs had significantly elevated levels of both CD14(Neg) and CD14(Pos) MDSC subsets (P < 0.001), while CKD patients and ICI-SCC(Pos) had significantly elevated levels of only the CD14(Neg)-MDSC subset. DC frequencies were significantly decreased in RTRs and CKD patients but were at normal levels in ICI-SCC(Pos). The MDSC/DC ratio was significantly elevated (P < 0.05) in RTRs (median = 5.7), CKD patients (median = 3.2) and ICI-SCC(Pos) (median = 3.5) relative to NDs (median = 0.7). The use of immunosuppressive drugs in CKD patients and past/current occurrence of SCC in RTRs was associated with significantly increased CD14(Neg)-MDSC frequencies. MDSC enriched from RTRs, when co-cultured with activated NDs T cells significantly suppressed extracellular IL-10 levels and can, when activated with formyl-methionyl-leucyl-phenylalanine, inhibit T-cell proliferation. CONCLUSIONS: RTRs, CKD patients and ICI-SCC(Pos) have increased MDSC frequencies and MDSC/DC ratios. These changes may impact on cancer immunosurveillance. Therefore, MDSC represent both a potential therapeutic target and prognostic marker in these patients, with respect to the development of SCC and other malignancies.

Asking the right question and finding the right answers.

Clinical consultations generate questions that can be informed by published (and unpublished) evidence. This is the basis for evidence-based practice. Finding answers involves searching available electronic databases. We describe a method for rephrasing or 'framing' clinical questions into population, intervention, comparator and outcome terms that helps to determine the best type of study to search for, and aids in the design of search strategies.

How to get the most from the medical literature: searching the medical literature effectively.

Different clinical questions are best answered using different study designs. This paper describes the best methods for finding relevant studies for well-framed clinical questions. We focus on which database is best to search to answer your question, describe the structure of effective search strategies and explore ways to develop appropriate search terms. We illustrate these with sensitive and specific search strategies to answer different clinical questions arising from a hypothetical clinical scenario typical of a nephrologist's everyday practice.

Antihypertensive treatment for kidney transplant recipients.

BACKGROUND: In some nontransplant populations, effects of different antihypertensive drug classes vary. Relative effects in kidney transplant recipients are uncertain. OBJECTIVES: To assess comparative effects of different classes of antihypertensive agents in kidney transplant recipients. SEARCH STRATEGY: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, conference proceedings and reference lists of identified studies were searched. SELECTION CRITERIA: Randomised controlled trials of any antihypertensive agent applied to kidney transplant recipients for at least two weeks were included. DATA COLLECTION AND ANALYSIS: Data was extracted by two investigators independently. Study quality, transplant outcomes and other patient centred outcomes were assessed using random effects meta-analysis. Risk ratios (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, both with 95% confidence intervals (CI) were calculated. Stratified analyses and meta-regression were used to investigate heterogeneity. MAIN RESULTS: We identified 60 studies, enrolling 3802 recipients. Twenty-nine studies (2262 participants) compared calcium channel blockers (CCB) to placebo/no treatment, 10 studies (445 participants) compared angiotensin converting enzyme inhibitors (ACEi) to placebo/no treatment and seven studies (405 participants) compared CCB to ACEi. CCB compared to placebo/no treatment (plus additional agents in either arm as required) reduced graft loss (RR 0.75, 95% CI 0.57 to 0.99) and improved glomerular filtration rate (GFR), (MD, 4.45 mL/min, 95% CI 2.22 to 6.68). Data on ACEi versus placebo/no treatment were inconclusive for GFR (MD -8.07 mL/min, 95% CI -18.57 to 2.43), and variable for graft loss, precluding meta-analysis. In direct comparison with CCB, ACEi decreased GFR (MD -11.48 mL/min, 95% CI -5.75 to -7.21), proteinuria (MD -0.28 g/24 h, 95% CI -0.47 to -0.10), haemoglobin (MD -12.96 g/L, 95% CI -5.72 to -10.21) and increased hyperkalaemia (RR 3.74, 95% CI 1.89 to 7.43). Graft loss data were inconclusive (RR 7.37, 95% CI 0.39 to 140.35). Other drug comparisons were compared in small numbers of participants and studies. AUTHORS' CONCLUSIONS: These data suggest that CCB may be preferred as first line agents for hypertensive kidney transplant recipients. ACEi have some detrimental effects in kidney transplant recipients. More high quality studies reporting patient centred outcomes are required.

Antihypertensives for kidney transplant recipients: systematic review and meta-analysis of randomized controlled trials.

In nontransplant populations, effects of different antihypertensive drug classes vary. Relative effects in kidney transplant recipients are uncertain. We performed a systematic review including random effects meta-analysis of randomized controlled trials, using Cochrane Collaboration methodology. We identified 60 trials, enrolling 3802 recipients. Twenty-nine trials (2262 patients) compared calcium channel blockers (CCB) with placebo or no treatment, 10 trials (445 patients) compared angiotensin-converting enzyme inhibitors (ACEi) with placebo or no treatment, and seven studies (405 patients) compared CCB with ACEi. CCB compared with placebo or no treatment (plus additional agents in either arm as required) reduced graft loss (risk ratio [RR] 0.75, 95% confidence intervals [CI] 0.57-0.99) and improved glomerular filtration rate (GFR; mean difference [MD] 4.5 mL/min, 95% CI 2.2-6.7). Data on ACEi versus placebo or no treatment were inconclusive for GFR (MD -8.1 mL/min, 95% CI -18.6-2.4) and inconsistent for graft loss, precluding meta-analysis. In direct comparison with CCB, ACEi decreased GFR (MD 11.5 mL/min, 95% CI 7.2-15.8), proteinuria (MD 0.28 g/day, 95% CI 0.10-0.47), hemoglobin (MD 11.5 g/L, 95% CI 7.2-15.8), and increased hyperkalemia (RR 3.7, 95% CI 1.9-7.7). Graft loss data were inconclusive (RR 7.4, 95% CI 0.4-140). These data suggest that CCB may be preferred as first-line agents for hypertensive kidney transplant recipients.

Diagnostic accuracy of blood qualitative nucleic acid testing for polyomavirus-associated nephropathy in kidney recipients.

AIM: Polyomavirus-associated nephropathy (PVAN) is an important cause of graft loss following kidney transplantation and may only be diagnosed with kidney transplant biopsy. Early detection may improve outcomes by enabling early intervention. Serum polyomavirus polymerase chain reaction (PVPCR) has been used to identify patients at risk of PVAN, but prior studies have not assessed all patients with negative PVPCR with transplant biopsy, potentially overestimating test performance. METHODS: We assessed the diagnostic accuracy of qualitative PVPCR for detection of PVAN in a population undergoing protocol biopsies. We included all patients receiving kidney or kidney-pancreas transplants and followed at Westmead Hospital, Sydney, Australia, between May 2002 and March 2007, excluding those with graft loss prior to 1 month post transplant or without PVPCR testing in the first 12 months. We compared PVPCR to contemporaneous transplant biopsies assessed with light microscopy and immunohistochemistry. RESULTS: Of the 257 included patients, 246 (96%) underwent biopsy within 30 days of PVPCR. Eight of 36 patients with positive PVPCR had PVAN and one of 210 patients with negative PVPCR had PVAN. The point prevalence of PVAN was therefore 3.7%, with PVPCR sensitivity 89% (95% CI 57% to 99%) and specificity 88%(95% CI 83% to 92%). The negative predictive value is 99.5% (95% CI 97.3% to 100.0%). CONCLUSION: Qualitative PVPCR on serum is a reliable triage test for excluding the presence of PVAN. Screening for PVAN need not include biopsy in patients with negative PVPCR.